PROJECT SUMMARY/ABSTRACT The social and economic environment in which we live has a major impact on our physical and mental health and risk of developing diseases ranging from cancer to major depressive disorder to heart disease. Alzheimer's disease (AD) is the 6th leading cause of death and a major, and rising, contributor to health care expenditures in the United States. Socioeconomic disparities exist in the diagnosis, treatment and outcomes related to AD and socioeconomic disadvantage is a risk factor for developing Alzheimer's disease and dementia. Understanding how exposure to socioeconomic disadvantage leads to increased AD risk could provide insight into new treatment and prevention efforts targeted at the most vulnerable populations. Despite this critical need, the neurobiological mechanisms that underlie the relationship between socioeconomic disadvantage and AD are currently unknown. To address this understudied topic, the proposed project will couple a validated, multi-dimensional index of neighborhood-level socioeconomic disadvantage with a rich longitudinal dataset including state of the art neuroimaging, cognitive testing and biochemical data from the Wisconsin Registry for Alzheimer's disease Prevention (WRAP) and Wisconsin Alzheimer's Disease Research Center study cohorts. Preliminary data generated for this project suggests that exposure to high levels of neighborhood-level socioeconomic disadvantage in cognitively unimpaired late-middle aged adults is associated with worse performance on a memory task, decreased volume of the hippocampus (a brain structure critical for memory processes) and elevated levels of AD biomarkers in the cerebral spinal fluid. These findings suggest a relationship between high levels of neighborhood disadvantage and pre-clinical Alzheimer's disease pathology in late middle age, a time of increased risk for eventually developing AD. The proposed project will specifically interrogate the relationship between exposure to neighborhood disadvantage in late-middle age and 1) longitudinal decline in performance on memory-related cognitive tasks, 2) longitudinal atrophy in associated memory- related brain regions and microstructural white matter changes in tracts connected to those regions and 3) how AD pathology (amyloid and tau) moderates these relationships. The results of this study will provide insight into the relationship between exposure to neighborhood socioeconomic disadvantage during late middle age and preclinical AD. These studies will lay the groundwork for subsequent mechanistic studies of these relationships and can help inform policy targeted at ameliorating disparities in Alzheimer's disease.